Alzheimer's disease and periodontitis are highly prevalent diseases worldwide. A previous study showed(Holmer et al., 2018) that periodontitis is strongly associated with cognitive impairment (CI) and Alzheimer's disease (AD) and is one of the important risk factors for Alzheimer's disease. The risk increases progressively as the disease progresses, making it necessary to explore the molecular mechanisms of both diseases and to find early targets to prevent disease progression.
In this study, by searching the datasets of Alzheimer's disease and periodontitis in GEO, we identified 16 common differential genes between these two diseases. We also performed GO and KEGG pathway enrichment analysis and constructed a PPI network to identify the top 6 HUB genes from the differential genes. We also validated the diagnostic value of these 6 HUB genes for patients with Alzheimer's disease and periodontitis. The results suggest that these 6 HUB genes may be important in predicting the risk of Alzheimer's disease and periodontitis.
The CD4 molecule is expressed primarily on the surface of mature CD4 cells. This gene encodes the CD4 membrane glycoprotein of T lymphocytes.CD4 antigen acts as a co-receptor with the T cell receptor on T lymphocytes to recognize antigens displayed by antigen presenting cells in the class II MHC molecular environment(J. Chen et al., 2022). The CD4 antigen is also the primary receptor for human immunodeficiency virus entry through interaction with the HIV Env gp120 subunit. The gene is expressed not only in T lymphocytes, but also in B cells, macrophages, granulocytes, and various regions of the brain. The protein functions to initiate or enhance the early stages of T-cell activation and may act as an important mediator of indirect neuronal injury in infectious and immune-mediated diseases of the central nervous system(Chen, Barr, Zuk, Gorman, & Colgan, 2022). Diseases associated with CD4 include immunodeficiency 79 and Okt4 epitope defects(Dong et al., 2022). No studies have yet shown a relationship between CD4 and Alzheimer's disease and periodontitis.
KDR (kinase insertion domain receptor) is a protein-coding gene. Its related pathways include GPCR pathway and Hippo-Merlin signaling dysregulation. An important paralog of this gene is FLT1. tyrosine protein kinase that acts as a cell surface receptor for VEGFA, VEGFC, and VEGFD and plays an important role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis by promoting the proliferation, survival, migration, and differentiation of endothelial cells and facilitating the reorganization of the actin cytoskeleton(Chamnanya et al., 2022; Fagbohun et al., 2022; Modak & Saha, 2022; Saoud, Aflouk, Ben Afia, Gaha, & Bel Hadj Jrad, 2022). Diseases associated with KDR include hemangiomas, infantile capillary hemangiomas, and cluster hemangiomas(X. Li et al., 2017; Y. Li, Xia, & Jin, 2007).
CXCR4 encodes a CXC chemokine receptor specific for stromal cell-derived factor-1. The protein has seven transmembrane regions and is located on the cell surface. It acts with the CD4 protein to support HIV entry into cells and is also highly expressed in breast cancer cells(Kotb, Ibrahim, Mostafa, & Shahin, 2022; L. Li, Chen, Yu, Zhang, & Chen, 2022). Diseases associated with CXCR4 include WHIM (warts, hypogammaglobulinemia, infection and osteomyelitis) syndrome and macroglobulinemia(Garcia-Cuesta et al., 2022; Luo, De Pascali, Richmond, Khojah, & Benovic, 2022). Recent studies have also shown that CXCR4 is associated with periodontitis, for example, CXCR4 antagonists inhibit periodontal bone loss due to periodontitis(McIntosh & Hajishengallis, 2012), CXCR4 signaling contributes to alveolar bone resorption in Porphyromonas gingivalis-induced periodontitis in mice(McIntosh & Hajishengallis, 2012), CXCR4 signaling in macrophages contributes to periodontal mechanical hypersensitivity in Porphyromonas gingivalis-induced periodontitis in mice(Nagashima et al., 2017).
CXCL12 is a protein-coding gene that encodes an endocrine family of stromal cell-derived alpha chemokines submembers. The encoded protein acts as a G protein-coupled receptor, chemokine (C-X-C motif) receptor4 ligands that function in many different cellular functions, including embryogenesis, immune surveillance vision, inflammatory response, tissue homeostasis, and tumor growth and metastasis(Barinov et al., 2017; B. Li et al., 2018; Ruscher et al., 2013). CXCL12 is associated with the diseases include human immunodeficiency virus type 1 and ischemia(Bachelerie, 2010; Riek-Burchardt et al., 2010). There are also recent studies showing an association between CXCL12 associated with periodontitis, for example: in a mouse model of Pseudomonas gingivalis-induced periodontitis, CXCL12 in expression is upregulated in Pseudomonas aeruginosa infection in periodontitis(Hernandez et al., 2011). CXCL12 promoter DNA methylation status in periodontal play an important role in the development of disease(Grdovic et al., 2016) .
JAK2 encodes a non-receptor tyrosine kinin that plays a central role in cytokine and
growth factor signaling enzymes. Mutations in this gene are associated with many myeloproliferative disorders, malignancies, true erythropoietic disorders, thrombocytosis, and JAK2 was one of the first diagnostic markers for the diagnosis of myeloproliferative disorders(Van Egeren et al., 2022; Zhang, Tu, Sha, & Qian, 2022). The V617F mutation is the most clinically relevant variant, seen in approximately half of all myeloproliferative disorders. This variant is a known activating mutation, and activated JAK2 is sufficient to drive myeloproliferative disease in mouse models.V617F, although the most common, is not the only mechanism by which JAK2 is activated in patients. The gene is also a downstream target of the cytokine IL6, which is produced by B cells, T cells, dendritic cells, and macrophages to generate an immune response or inflammation(Feng et al., 2022; Zhou, Chen, Yao, & Gu, 2022). Dysregulation of the IL6/JAK2/STAT3 signaling pathway leads to abnormal proliferation of hematopoietic stem cells and myeloproliferative neoplasms(Jin et al., 2022).
The protein encoded by the PTPN11 gene is a member of the protein tyrosine phosphatase (PTP) family. PTP is known to be a signaling molecule that regulates a variety of cellular processes, including cell growth, differentiation, mitotic cycle, and oncogenic transformation(Macia et al., 2022). This PTP is widespread in most tissues. This PTP is widely expressed in most tissues and plays a regulatory role in a variety of cellular signaling events important for many cellular functions, such as mitotic activation, metabolic control, transcriptional regulation, and cell migration(Liu et al., 2016; Wang et al., 2009). Mutations in this gene are the cause of Noonan syndrome and acute myeloid leukemia(Fobare et al., 2022; Wang et al., 2009).
We also evaluated relevant gene biological functions and pathways, such as GO enrichment analysis of the tumor necrosis factor signaling pathway, inflammatory response and immune system disease pathways, reported to be closely associated with both diseases.